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Matthias M. Falk , Ph.D.
Associate Professor
Cell Biology

Dept. of Biological Sciences
111 Research Drive
Iacocca Hall, #D218
Lab #C250
phone: 610-758-5896
(610) 758-4004 fax
mfalk@lehigh.edu

In the News

Microscopic photographs taken by Lehigh’s Matthias Falk were featured in a unique exhibition at a San Francisco art gallery ... learn more

Research Interests

Membrane Protein Biosynthesis, Structure & Function of Gap Junctions and other Cell-Cell Junctions, Microscopy

Research Summary

Cells of multi-cellular organisms are autonomous units, yet constantly depend on signals from their surrounding. Signals can either be transmitted between cells and the extra-cellular milieu, or directly from cell to cell. Information exchange is mediated by membrane proteins that assemble into localized, spatial and temporal organized multiunit transmembrane protein complexes, such as tight junctions, adherens junctions, desmosomes, focal adhesions, hemi-desmosomes, chemical synapses, immunological synapses, and gap junctions. We are interested in understanding how such complex signaling structures are biosynthesized, how they are structured, and how their function is regulated.

Gap junctions are the only known cellular structures that allow a direct transfer of signaling molecules from cell-to-cell by forming hydrophilic channels that bridge the opposing plasma membranes of neighboring cells. The crucial role of gap junction mediated intercellular communication (GJIC) for coordination of development, tissue function, and cell-homeostasis is now well documented; and mutations in gap junction channel protein encoding genes can result in a number of diseases, that include deafness, cataracts, severe dermatological disorders, and cancer. In addition, recent findings indicate that GJIC also plays a significant role in transient cell-cell contacts, and that gap junction hemi-channels (connexons) by themselves can function in intra/extra-cellular signaling.

Biosynthesis of these channels is a complicated, highly regulated process. Over the past decade we have studied where and how the gap junction channel proteins (connexins) are synthesized, elucidated gap junction channel subunit compatibility, characterized signals that regulate subunit interaction, determined cellular components involved in these processes, characterized how newly synthesized gap junction channels are trafficked to the plasma membrane, and have investigated how gap junctions are assembled.

Our research plan is based on an integrated approach that combines novel high resolution and live-cell imaging techniques with molecular biology, biochemistry, immunological, and functional assays. Proteins are analyzed in cell-free expression systems, in tissues, and especially in cultured living cells. Four aspects of gap junction structure and function are of current interest: (1) The characterization of molecular signals that regulate composition of gap junctions and gap junction channels. (2) To investigate the degradation process of gap junctions and what role this process might have for the direct spread of viral pathogens between cells. (3) To investigate the cause of human disorders that correlate with point mutations in a and b connexins; and (4) to characterize other cellular components and their role in gap junction assembly and function.

Recent Publications

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Wang, S., Kowal, T.J., Marei, M.K, Falk, M.M., and Jain, H. 2013. Nanoporosity significantly enhances the biological performance of engineered glass scaffolds. Tissue Engineering Part A (in press)

Thévenin, A.F. Kowal, T.J., Fong, J.T., Kells, R.M., Fisher, C.G., and Falk, M.M. 2013. Proteins and mechanisms regulating gap junction assembly, internalization and degradation. Physiology 28:93-116.

Baker, S.M, and Falk, M.M. 2012. Natural inflammatory mediators thrombin and endothelin modulate gap junction intercellular communication and cell-cell adhesion. eBook. Nova Science Publishers, Inc., Hauppauge, NY, USA (ISBN: 978-1-62417-375-2).

Falk, M.M., Fong, J.T., Kells, R.M., O'Laughlin, M.C., Kowal, T.J., Thévenin, A.F. 2012. Degradation of endocytosed gap junctions by autophagosomal and endo-/lysosomal pathways: a perspective. J. Membr. Biol. 245:465-76.

Fong, J.T., Kells, R.M., Gumpert, A.M., Marzillier, J.Y., Davidson, M.W. and Falk, M.M. 2012. Internalized gap junctions are degraded by autophagy. Autophagy 8:794-811. (Evaluated by ‘Faculty of 1000’)

Baker, S.M., and Falk, M.M. 2012. Chapter 18: Thrombin-mediated regulation of gap junction intercellular communication and cell-to-cell adhesion, pp. 247-254. In Thrombin: Function and Pathophysiology, Th. Stief (Ed.), Nova Science Publishers, Inc., Hauppauge, NY, USA (ISBN: 978-1-61942-087-8).

Jain, R.H., Marzillier, J.Y., Kowal, T.J., Wang, S., Jain, H., and Falk, M.M. 2011. Expression of mineralized tissue-associated proteins is highly upregulated in MC3T3-E1 osteoblasts grown on a borosilicate glass substrate. Advances in Bioceramics and Porous Ceramics IV: Ceramic Engineering & Science Proceedings, R. Narayan & P. Colombo (Eds.) vol. 32 (6):111-122.

Wang, S., Falk, M.M., Rashad, A., Saad, M.M., Marques, A.C., Almeida, R.M., Marei, M.K., and Jain, H. 2011. Evaluation of 3D nano-macro porous bioactive glass scaffold for hard tissue engineering. J. Mater. Sci: Mater. Med. 22:1195-1203.

Govindarajan, R., Chakraborty, S., Johnson, K.E., Falk, M.M., Wheelock, M.J., Johnson, K.R., and Mehta, P.P. 2010. Assembly of connexin43 into gap junctions is regulated differentially by E-cadherin and N-cadherin in rat liver epithelial cells. Mol. Biol. Cell 21:4089-4107.

Vueva, Y., Gama, A., Almeida, R., Wang S., Jain, H., and Falk, M.M. 2010. Monolithic glass scaffolds with dual porosity prepared by polymer-induced phase separation and sol-gel. J. Americ. Ceramic Soc. 93(7):1945-1949.

Falk, M.M. 2010. Adherens junctions remain dynamic. BMC Biology 8:34-37.

Baker, S.M., R.W. Buckheit III, and Falk, M.M. 2010. Green-to-red photoconvertible fluorescent proteins: tracking cell and protein dynamics on standard wide-field mercury arc-based microscopes. BMC Cell Biology 11:15-24. (Evaluated by ‘Faculty of 1000’) (highly accessed)

Chakraborty, S., S. Mitra, M.M. Falk, S. Caplan, M.J. Wheelock, K.R. Johnson; and P.M. Mehta. 2010. E-Cadherin Differentially Regulates the Assembly of Connexin43 and Connexin32 into Gap Junctions in Human Squamous Carcinoma Cells. J. Biol. Chem. 285:10761-10776.

Jain, R.H., Wang, S., Moawad, H., Falk, M.M., Jain, H. 2010. Glass Bone Implants: The Effect of Surface Topology on Attachment and Proliferation of Osteoblast Cells on 45S Bioactive Glass. In Engineering Biomaterials for Regenerative Medicine; S. Bhatia, S. Bryant, J.A. Burdick, J.M. Karp, K. Walline (Eds.). Mater. Res. Soc. Symp. Proc. Vol. 1235, Warrendale, PA, 1235-RR03-47 (6 pages).

Marques, A., Almaida, R., Thima, A., Falk, M.M., Jain, H. 2009. Sol-gel derived glass scaffold with high pore interconnectivity and enhanced bioactivity. J. Materials Res., 24:3495-3502.

Moawad, H.M., Wang, S., Jain, H., Falk, M.M. 2009. Effect of zinc on bioactivity of nano-macroporous soda-lime phosphofluorosilicate glass-ceramics. Ceramic Engineering & Science Proceedings, Vol. 30, Issue 6, pp. 179-190.

Falk, M.M. S. Baker, A.M. Gumpert, D. Segretain, and R.W. Buckheit III. 2009. Gap junction turnover is achieved by the internalization of small endocytic double-membrane vesicles. Mol. Biol. Cell 20:3342-3352. (Evaluated by ‘Faculty of 1000’)

Gilleron, J., C. Fiorini, D. Carette, C. Avondet, M.M. Falk, D. Segretain, and G. Pointis. 2008. Molecular reorganization of Cx43, ZO-1, and c-Src interactions during HCH-induced internalization of gap junctions. J. Cell Sci. 121:4069-4078.

Baker, S.M., N. Kim, D. Segretain, and M.M. Falk. 2008. Acute internalization of gap junctions in vascular endothelial cells in response to inflammatory mediator-induced G-protein coupled receptor activation. FEBS Lett. 582:4039-4046 (Including Journal Issue Cover).

Gumpert, A.M., J.S. Varco, S.M. Baker, M. Piehl, and M.M. Falk. 2008. Double-membrane gap junction internalization requires the clathrin-mediated endocytic machinery. FEBS Lett. 582, 2887-2892.

Iovine, M.K., A.M. Gumpert, M.M. Falk, and T.C. Mendelsohn. 2008. Cx23, a connexin with only four extracellular-loop cysteines, forms functional gap junction channels and hemichannels. FEBS Lett. 582:165-170.

Gilleron, J., D., Segretain, and M.M. Falk. 2007. Gap junction trafficking and regulation. Reactome: a curated knowledgebase of biological pathways. Cold Spring Harbor Laboratory, European Bioinformatics Institute, and GO Consortium.http://www.reactome.org

Piehl, M., C. Lehmann, A. Gumpert, J.-P. Denizot, D. Segretain, and M.M. Falk. 2007. Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process. Mol. Biol. Cell 18:337-347. (Evaluated by ‘Faculty of 1000’)

Eastman, S. D., T. H. Chen, M. M. Falk, T. C. Mendelson, and M. K. Iovine. 2006. Phylogenetic analysis of three complete gap junction gene families reveals lineage-specific duplications and highly supported gene classes. Genomics. 2006 Feb; 87(2):265-74.

Segretain, D, and M.M. Falk, 2004. Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim. Biophys. Acta 1662, 3-21.

Lagrée, V., K. Brunschwig, P. Lopez, N. B. Gilula, G. Richard, and M.M. Falk. 2003. Specific amino acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43. J. Cell Science 116, 3189-3201.

Falk, M. M. 2002. Genetic tags for labelling live cells: gap junctions and beyond. Trends Cell Biol. 12:399-404.

Lauf, U., B.N.G. Giepmans, P. Lopez, S. Braconnot, S.-C. Chen, and M.M. Falk. 2002. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Proc. Natl. Acad Sci. USA 99:10446-10451.
(On-Line Movies at: http://www.pnas.org/cgi/content/full/162055899/DC1)

Falk, M. M. 2001. Connexins/Connexons: Cell-free expression. Methods Mol. Biol. 154:91-116.

Giepmans, B.N.G., I. Verlaan, T. Hengeveld, M.M. Falk, and W.H. Moolenaar. 2001. Gap junction protein connexin-43 interacts directly with microtubules. Current Biol. 11:1364-1368.

Lauf, U., P. Lopez, and M.M. Falk. 2001. Expression of fluorescently tagged connexins: a novel approach to rescue function of oligomeric DsRed-tagged proteins. FEBS Lett. 498:11-15.

Falk, M.M. and U. Lauf. 2001. High-resolution fluorescence deconvolution microscopy and tagging with the autofluorescent tracers CFP, GFP, and YFP to study the structural composition of gap junctions in living cells. Microsc. Res. Tech. 52:251-262.

Falk, M. M. 2000. Cell-free synthesis for analyzing the membrane integration, oligomerization, and assembly characteristics of gap junction connexins. Methods 20:165-179.

Falk, M.M. 2000. Connexin-specific distribution within gap junctions revealed in living cells. J. Cell Sci. 113:4109-4120.
(On-Line Movies at: http://jcs.biologists.org/cgi/content/full/113/22/4109/DC1)

Falk, M.M. 2000. Biosynthesis and structural composition of gap junction intercellular membrane channels. Eur. J. Cell Biol. 79:564-574.

Falk, M. M. and N. B. Gilula. 1998. Connexin membrane protein biosynthesis is influenced by polypeptide positioning within the translocon and signal peptidase access. J. Biol. Chem. 273:7856-7864.

Kahn, T.W., R.N. Beachy, and M.M. Falk. 1997. Cell-free expression of a GFP fusion protein allows quantitation in vitro and in vivo. Current Biol. 7:R207-R208.

Falk, M.M., L.K. Buehler, N.M. Kumar, and N.B. Gilula. 1997. Cell-free Synthesis and Assembly of Connexins into Functional Gap Junction Membrane Channels. EMBO J. 16:2703-2716.

Falk, M.M., N.M. Kumar, and N.B. Gilula. 1994. Membrane Insertion of Gap Junction Connexins: Polytopic Channel Forming Membrane Proteins. J. Cell Biol. 127:343-355.

CV

Since 8/03	Assistant Professor, Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania, USA
2/98-8/03	Assistant Professor, Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA
7/96-2/98	Senior Research Associate, Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA
4/92-7/96	Postdoctoral Fellow, Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA Sponsor: Dr. Norton B. Gilula Project title: Structure and function of gap junction membrane channels
12/91	Ph.D. Defense, Curriculum in Molecular Biology, Cell Biology, Virology, and Biochemistry, University of Heidelberg, Heidelberg, Germany
11/87-2/92	Ph.D. thesis, Center for Molecular Biology (ZMBH), University of Heidelberg, Heidelberg, Germany Thesis Advisor: Dr. E. Beck; chair: Dr. H. Schaller Thesis project: Structure and function of foot-and-mouth disease virus (Picornaviridae) proteins
11/87	Diploma in Biology (M.A.), University of Giessen, Giessen, Germany
10/86-11/87	Diploma thesis, Department of human virology, University of Giessen, Giessen, Germany Thesis Advisor: Dr. H. Niemann, chair: Dr. H. Bauer Thesis project: Characterization of Golgi retention signals in the E1 transmembrane glycoprotein of MHV (Coronaviridae)
5/84	Vor-Diplom in Biology (B.A.), University of Giessen, Giessen, Germany
10/82-10/86	Studied Biology at the University of Giessen, Giessen, Germany